LARGE SIMPLE TRIALS AND KNOWLEDGE
GENERATION IN A LEARNING HEALTH SYSTEM
An Institute of Medicine Workshop
November 26–27, 2012
500 Fifth Street NW, Washington, DC
Roundtable on Value & Science-Driven Health Care
Forum on Drug Discovery, Development, and Translation
1. Explore accelerating the use of large simple trials (LSTs) to improve the speed and practicality of knowledge generation for medical decision making and medical product development;
2. Consider the concepts of LST design, examples of successful LSTs, the relative advantages of LSTs, and the infrastructure needed to build LST capacity as a routine function of care;
3. Identify structural, cultural, and regulatory barriers hindering the development of an enhanced LST capacity and discuss needs and strategies in building public demand for, and participation in, LSTs; and
4. Suggest near-term strategies for accelerating progress in the uptake of LSTs in the United States.
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Appendix A Workshop Agenda LARGE SIMPLE TRIALS AND KNOWLEDGE GENERATION IN A LEARNING HEALTH SYSTEM An Institute of Medicine Workshop November 26–27, 2012 Room 100 Keck Center 500 Fifth Street NW, Washington, DC Roundtable on Value & Science-Driven Health Care Forum on Drug Discovery, Development, and Translation Meeting Objectives 1. Explore accelerating the use of large simple trials (LSTs) to improve the speed and practicality of knowledge generation for medical decision making and medical product development; 2. Consider the concepts of LST design, examples of successful LSTs, the relative advantages of LSTs, and the infrastructure needed to build LST capacity as a routine function of care; 3. Identify structural, cultural, and regulatory barriers hindering the development of an enhanced LST capacity and discuss needs and strategies in building public demand for, and par- ticipation in, LSTs; and 4. Suggest near-term strategies for accelerating progress in the uptake of LSTs in the United States. 65
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66 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM Monday, November 26 1:00 pm Welcome, Introductions, and Overview Welcome, framing of the meeting, and agenda overview o Michael McGinnis (Institute of Medicine) o avid L. DeMets (Planning Committee Co-Chair, D University of Wisconsin School of Public Health) o ichard E. Kuntz (Planning Committee Co-Chair, R Medtronic) 1:15 pm Introduction to Large Simple Trials David L. DeMets (Planning Committee Session chair: Co-Chair, University of Wisconsin School of Public Health) Session Objectives: Ø o et the vision for large simple trials (LSTs) as part of a S learning health care system. o iscuss the advantages of LSTs over current trial D approaches. o iscuss opportunities for LSTs as way to embed trials D in growing digital infrastructure. Presentations: Ø o vision for LSTs in the learning health system A Michael S. Lauer (National Heart, Lung, and Blood Institute) o pportunities and challenges for LSTs O Ralph I. Horwitz (GlaxoSmithKline) Session Questions: Ø 1. What is an LST? 2. How would these trials fit into the larger clinical re- search ecosystem in a learning health care system? 3. What need would this approach to clinical trials fill? (randomized controlled trial [RCT] cost, efficiency, generalizability) 4. What are the advantages/disadvantages to this ap- proach? (heterogeneity, subgroup analysis) 5. How does the increased adoption of electronic health records (EHRs) provide an opportunity for LSTs? 6. Are there modifications to the current design and con- duct of LSTs that would enhance their value to a learn- ing health system?
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APPENDIX A 67 7. What are some exampleas of the areas still in need of work to realize this vision (e.g., the culture shift needed to adopt potentially disruptive technologies)? Q&A and Open Discussion 1:55 pm Highlighted Examples of LSTs Session chair: James B. Young (Cleveland Clinic) Session Objectives: Ø o ighlight four examples of LSTs that each exemplify a H different defining characteristic of LSTs. o mphasize trade-offs in trial design by discussing the E pros and cons, giving examples of how these play out, and suggesting alternative approaches. o oreshadow the rest of the workshop by asking F LST example speakers to address their experiences (successes and failures) with stakeholder engagement, infrastructure, and policy. Ø Presentations: o ery large, population-based trial with broad inclusion V criteria, high cost-efficiency, and hybrid design (mail- based plus in-clinic component) § VITamin D and omegA 3 triaL (VITAL) JoAnn E. Manson (Harvard University) o rial assessing role of waiving medication copayments T for improving drug adherence and health outcomes, collaboration with health insurance company (Aetna) § ost-Myocardial Infarction Free Rx Event and P Economic Evaluation (MI FREEE) trial Niteesh K. Choudhry (Brigham and Women’s Hospital) o luster randomized trial involving pediatric practices, C utilization of EHR and decision support tools for obesity interventions § igh Five for Kids Trial/Study of Technology to H Accelerate Research (STAR) Elsie M. Taveras (Harvard Pilgrim Health Care Institute)
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68 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM o Industry trial for regulatory approval with global component § eart Outcomes Prevention Evaluation (HOPE) H trial P. J. Devereaux (McMaster University) Session Questions: Ø 1. Please give a very brief introduction on the specifics of the trial and why it is considered an LST. 2. How does the trial address the issues of the general- izability of the evidence produced, simplification of research processes, and cost-effectiveness? 3. In retrospect, what were the risks and trade-offs as- sociated with the choice of an LST design (e.g., the risk of not collecting data that could be subsequently requested)? Please discuss the pros and cons, giving examples of how these play out and suggesting alter- native approaches and any design changes that you would make on the basis of the lessons learned. 4. What were your team’s experiences (successes and failures) with the following issues, which will be discussed in further detail during the course of the workshop: a. Stakeholder (health system leader, clinician, pa- tient) engagement b. Infrastructure (research infrastructure, health in- formation technology) c. Policy (privacy, consent, institutional review board issues, regulatory issues) Q&A and Open Discussion 3:15 pm Break 3:30 pm Partners Perspectives on LST Uptake Joe V. Selby (Patient-Centered Outcomes Session chair: Research Institute) Session Objectives: Ø o Identify stakeholders relevant to the increased use of LSTs, focusing on patients, clinicians/health care systems, and payers, and the incentives that they face that could impede or advance uptake.
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APPENDIX A 69 o ngage in the issues of the most importance to E stakeholders and deliberate on what it will take from each of their respective points of view. Presentations: Ø o atient perspective P Nancy Roach (Fight Colorectal Cancer) o ealth systems/clinician perspective H Alan S. Go (Kaiser Permanente) o ayer perspective P Lewis G. Sandy (UnitedHealth Group) Session Questions: Ø 1. What are the top three issues for patients/clinicians/ payers in considering the use of an LST approach to generate clinical evidence? 2. What are the top three considerations for patients and clinicians in contemplating the greater integra- tion of trials into routine care settings? 3. What are the top three priorities for raising the awareness and participation of patients and clini- cians in trials integrated into routine care? 4. What are your priorities regarding the types of evi- dence that can be generated through LSTs? 5. What are the roles for health systems and payers in (a) setting priorities, (b) dedicating staff support, and (c) providing funding for LSTs in routine care settings? Q&A and Open Discussion 4:30 pm Summary and Preview of Next Day 5:00 pm Adjourn Tuesday, November 27 8:00 am Coffee and light breakfast available 8:30 am Welcome, Brief Agenda Overview Welcome, framing of the meeting, and agenda overview o avid L. DeMets (Planning Committee Co-Chair, D University of Wisconsin School of Public Health) o ichard E. Kuntz (Planning Committee Co-Chair, R Medtronic)
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70 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM 8:45 am Infrastructure Needs Session chair: John J. Orloff (Novartis) Session Objectives: Ø o ighlight infrastructure needs and barriers to the H greater performance of LSTs. o iscuss the needs and potential approaches to merge D the goals of the health care system with research, focusing on the current state and future potential of the use of EHRs as platform for LSTs. o iscuss establishment and sustainability of trial D networks as an infrastructure to host and facilitate LSTs. Presentations: Ø o ligning care and research to reduce burdens and A improve integration Richard Platt (Harvard Pilgrim Health Care Institute) o oint-of-care trials using EHR platforms P Ryan E. Ferguson (VA Boston Healthcare System) o etting to comparable, computable data G Rebecca Daniels Kush (Clinical Data Interchange Standards Consortium) o uilding reusable research networks B Carole M. Lannon (Cincinnati Children’s Hospital Center) Session Questions: Ø 1. What are the current infrastructure needs for the more widespread performance of LSTs? Would you consider conducting LSTs on your network? 2. What opportunities and challenges in the use of EHRs as a platform for LSTs currently exist? What are the priorities for change to maximize this po- tential going forward? How can disruption to the delivery of health care be minimized to incentivize more practicing physicians to engage in knowledge generation? 3. What is the current state of the use of routinely col- lected clinical data for trials? What role will data standards play in the facilitation of LSTs? What are the priorities for change to maximize this potential going forward?
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APPENDIX A 71 4. What is the current state of reusable research net- works in the United States? What is their role in LSTs? What are the major opportunities and barriers to the reusable network approach? Are there alter- native community-based settings with lower infra- structure costs and greater access to patients that should be considered? Are existing research networks (including perhaps CTSA institutions or PBRNs) fit for purpose? What business models (e.g., hub and spoke) would be the most effective? Q&A and Open Discussion 10:45 am Break 11:00 am Policy Needs: Ethics, Trial Processes Session chair: Robert M. Califf (Duke University) Session Objectives: Ø o potlight and differentiate real and perceived policy S barriers to the greater use of LSTs. o ighlight examples of ways in which these have been H dealt with (or overcome). o nticipate potential policy issues as trials move to A leverage electronic systems. o uggest components of a policy framework that would S facilitate LSTs. Presentations: Ø o olicy overview P Robert M. Califf (Duke University) o thical issues of bringing research and care closer E together Ruth R. Faden (Johns Hopkins University) o rial process challenges (privacy, institutional review T boards) Deven McGraw (Center for Democracy and Technology)
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72 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM Session Questions: Ø 1. What are the major policy barriers to the more widespread performance of LSTs? How have these barriers been overcome in the past? What are the priorities for change going forward? 2. What are the important ethical issues to consider in bringing research and care closer together? What are the components of a new ethical framework to sup- port a learning health system? 3. What are the major privacy and human subjects research policy-associated considerations for LSTs? How have these challenges been overcome? What are the priorities for change going forward? 4. What are the relevant ethical and policy consider- ations associated with randomization without ad- ditional consent in situations of equipoise? Q&A and Open Discussion 12:00 pm Lunch Keynote Randomized Evaluations of Accepted Choices in Treatment (REACT) trials Tjeerd-Pieter van Staa (Clinical Practice Research Datalink, United Kingdom) Session Questions: Ø 1. What are the REACT trials? What was the impetus for these trials? How do they compare to LSTs? 2. What are the stakeholder engagement-related chal- lenges you have faced in setting up/running these trials? How have the relevant stakeholder groups responded? 3. What are the infrastructure-related challenges and opportunities you have faced? What role has the level of EHR adoption placed in facilitating or inhibiting them? What are the most crucial non- information technology infrastructure resources? 4. How have you addressed concerns about the ac- curacy and validity of data in the electronic medical record? 5. What are the policy-related challenges that you have faced? What are the differences between the UK and
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APPENDIX A 73 U.S. systems that have facilitated or impeded these challenges? 6. What lessons learned or best practices would you pass along to LST investigators? What would you do differently? Q&A and Open Discussion 1:00 pm Policy Needs: Medical Product Regulatory Issues Richard E. Kuntz (Planning Committee Co- Session chair: Chair, Medtronic) Presentations: Ø o rial complexity T Kenneth A. Getz (Tufts University) o implifying clinical trials S Christopher B. Granger (Duke University) o DA perspective F Rachel E. Sherman (Center for Drug Evaluation and Research, U.S. Food and Drug Administration) Session Questions: Ø 1. In general, what is the optimal role of LSTs in the medical products regulatory approval pathway? Are there areas of medical product development in which LSTs are not useful? 2. How can an understanding of those policy/regulatory issues that drive complexity in traditional RCTs and the strategies to counteract them be applied to the adoption and use of LSTs in medical products regula- tory contexts? 3. What are the real and perceived regulatory barri- ers hindering the development of an enhanced LST capacity? 4. What are some near-term strategies for accelerating progress in the uptake of LSTs in the United States? 5. What is the current thinking from the U.S. Food and Drug Administration in terms of how and when LSTs might be used without jeopardizing the medical products development process?
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74 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM Q&A and Open Discussion 2:00 pm Break 2:15 pm Strategies Going Forward David L. DeMets (Planning Committee Session chair: Co-Chair, University of Wisconsin School of Public Health) Session Objectives: Ø o Identify and discuss issues and key themes from the workshop. o onsider strategies and priorities for accelerating C progress in the uptake of LSTs in the United States. Ø rief Summaries and Key Stakeholder Perspectives from B the Workshop: o epresentatives from key stakeholders groups R will provide an overview of key themes and issues identified from their perspectives. § ederal funders—Michael S. Lauer (National Heart, F Lung, and Blood Institute) § ongovernmental funders—Robert E. Ratner N (American Diabetes Association) § .S. Food and Drug Administration—Bram U Zuckerman (Center for Devices and Radiological Health) § enters for Medicare & Medicaid Services C (CMS)—Rosemarie Hakim § rivate payers—William H. Crown (Optum) P § ndustry—Peter Held (AstraZeneca) I § atients—Kate Ryan (National Women’s Health P Network) § linical researchers—Elizabeth A. Chrischilles C (University of Iowa College of Public Health) Panel Questions: Ø 1. What are the themes of today’s presentations and discussions that have resonated most strongly with you? 2. Where do you see the most opportunity for the ap- plication of LSTs? What do you see to be the biggest barriers?
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APPENDIX A 75 3. What will it take to seize these opportunities and overcome the barriers? 4. Based on the presentations and discussions, can you identify issues that need to be resolved by others be- fore progress can be made? For example, as the lead of the Ethics and Processes section, can you identify critical needs in infrastructure or regulatory issues that need to be resolved before you can achieve your goals? 5. If you were granted one wish to move LSTs forward, what would that wish be? Q&A and Open Discussion 4:15 pm Next Steps Ø ession Description: The workshop will conclude with a S brief discussion and summary of next steps. 5:00 pm Adjourn
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